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Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer's disease animal model.
Cellular and Molecular Life Sciences ( IF 8 ) Pub Date : 2020-02-07 , DOI: 10.1007/s00018-020-03468-0
Balázs A Györffy 1, 2 , Vilmos Tóth 2, 3 , György Török 4, 5 , Péter Gulyássy 6 , Réka Á Kovács 3 , Henrietta Vadászi 3 , András Micsonai 1, 3 , Melinda E Tóth 7 , Miklós Sántha 7 , László Homolya 4 , László Drahos 6 , Gábor Juhász 2, 8 , Katalin A Kékesi 1, 2, 9 , József Kardos 1, 3
Affiliation  

Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer's disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instruments of widespread synapse loss because they can tag synapses with functional impairments leading to their engulfment by microglia. However, an exact understanding of the affected synaptic functions that predispose to complement-mediated synapse elimination is lacking. Therefore, we conducted systematic proteomic examinations on synaptosomes prepared from an amyloidogenic mouse model of Alzheimer's disease (APP/PS1). Synaptic fractions were separated according to the presence of the C1q-tag using fluorescence-activated synaptosome sorting and subjected to proteomic comparisons. The results raised the decline of mitochondrial functions in the C1q-tagged synapses of APP/PS1 mice based on enrichment analyses, which was verified using flow cytometry. Additionally, proteomics results revealed extensive alterations in the level of septin protein family members, which are known to dynamically form highly organized pre- and postsynaptic supramolecular structures, thereby affecting synaptic transmission. High-resolution microscopy investigations demonstrated that synapses with considerable amounts of septin-3 and septin-5 show increased accumulation of C1q in APP/PS1 mice compared to the wild-type ones. Moreover, a strong positive correlation was apparent between synaptic septin-3 levels and C1q deposition as revealed via flow cytometry and confocal microscopy examinations. In sum, our results imply that deterioration of synaptic mitochondrial functions and alterations in the organization of synaptic septins are associated with complement-dependent synapse loss in Alzheimer's disease.

中文翻译:

在阿尔茨海默氏病动物模型中,突触线粒体功能障碍和Septin积累与补体介导的突触损失有关。

伴随突触丧失的突触功能障碍代表了阿尔茨海默氏病的主要病理标志。细胞毒性淀粉样蛋白低聚物的过度积累被广泛认为是神经退行性病变的关键事件。某些补体成分是广泛的突触丧失的关键手段,因为它们可以标记突触功能受损的小胶质细胞。但是,缺乏对影响以补体介导的突触消除为先导的突触功能的确切了解。因此,我们对从阿尔茨海默氏病(APP / PS1)的淀粉样小鼠模型制备的突触体进行了系统的蛋白质组学检查。使用荧光激活的突触体分选方法根据C1q标签的存在分离突触级分,并进行蛋白质组学比较。结果通过富集分析提高了APP / PS1小鼠C1q标记突触中线粒体功能的下降,这已通过流式细胞仪进行了验证。此外,蛋白质组学结果揭示了septin蛋白家族成员水平的广泛改变,已知它们会动态形成高度组织化的突触前和突触后超分子结构,从而影响突触传递。高分辨率显微镜研究表明,与野生型相比,具有大量septin-3和septin-5的突触显示APP / PS1小鼠中C1q的积累增加。此外,流式细胞仪和共聚焦显微镜检查显示,突触间隔素3水平与C1q沉积之间存在明显的正相关。总而言之,我们的结果暗示突触线粒体功能的恶化和突触隔蛋白组织的改变与阿尔茨海默氏病中依赖补体的突触丧失有关。
更新日期:2020-02-07
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